Pharmaceutical compositions containing a halo-substituted 2-amino-benzylamine-morpholide or a salt thereof

ABSTRACT

ANTITUSSIVE AND RESPIRATION-STIMULATING PHARMACEUTICAL COMPOSITIONS CONTAINING AS AN ACTIVE INGREDIENT N-(2ACETYLAMINO-3,5-DIBROMO-BENZYL) - N - ETHYL -B - AMINOPROPIONIC ACID-MORPHOLIDE OR A NON-TOXIC ACID ADDITION SALT THEREOF, OR A COMPOUND OF THE FORMULA 1-((MORPHOLIN-4-YL)-CO-CH2-N(-R2)-CH2-),2-(R3-NH-),R1,   HAL-BENZENE   WHEREIN   HAL IS CHLORINE OR BROMINE, R1 IS HYDROGEN, CHLORINE OR BROMINE, R2 IS ALKYL OF 1 TO 4 CARBON ATOMS, PHENYL OR BENZYL, AND R3 IS HYDROGEN, ALKANOYL OF 2 TO 4 CARBON ATOMS, BENZOYL, CHLOROBENZOYL, METHOXYBENZOYL, NICOTINOYL OR ISONICOTINOYL,   OR A NON-TOXIC, PHORMACOLOGICALLY ACCEPTABLE ACID ADDITION SALT THEREOF.

United States Patent PHARMACEUTICAL COMPOSITIONS CONTAIN- ING A HALO-SUBSTITUTED Z-AMINO-BENZYL- AMINE-MORPHOLIDE OR A SALT THEREOF Gerd Kriiger, 'Biberach an der Riss, Otmar Zipp, Osnabruck, and Johannes Keck, Josef Nicki, Hans Machleidt, Gerhard Ohnacker, Robert Engelhorn, and Sigfrid Piischmann, Biberach an der Riss, Germany, assignors to Boehringer Ingelheim G.m.b-H., Ingelheim am Rhein, Germany No Drawing. Application Nov. 12, 1970, Ser. No. 88,985, now Patent No. 3,661,903, dated May 9, 1972, which is a continuation-in-part of abandoned application Ser. No. 872,778, Oct. 30, 1969, which in turn is a continuation-in-part of abandoned application Ser. No. 555,696, June 7, 1966. Divided and this application Dec. 9, 1971, Ser. No. 206,517

Claims priority, application Germany, June 8, 1965, P 15 18 375.2, Int. Cl. A61k 27/00 US. Cl. 424-248 12 Claims ABSTRACT OF THE DISCLOSURE Antitussive and respiration-stimulating pharmaceutical compositions containing as an active ingredient N-(Z- acetylamino-3,S-dibromo-benzyl) N ethyl B aminopropionic acid-morpholide or a non-toxic acid addition salt thereof, or a compound of the formula R1 Ra CHg-N\ 0 CHn-i-N b NEE-R:

Hal

wherein or a non-toxic, phormacologically acceptable acid addition salt thereof.

This is a division of copending application Ser. No. 88,985, filed Nov. 12, 1970, now US. Pat. 3,661,903, issued May 9, 1972, which in turn is a continuation-inpart of copending application Ser. No. 872,778, filed Oct. 30, 1969, now abandoned, which in turn is a continuation-in-part of application Ser. No. 555,696, filed June 7, 1966, now abandoned.

This invention relates to novel pharmaceutical compositions containing as an active ingredient a halo-substituted 2-amino-benzylamine-morpholide or an acid addition salt thereof, as well as to various methods of using these compositions to suppress the cough reflex and stimulate the respiration.

More particularly, the present invention relates to antitussive'and respiration-stimulating pharmaceutical compositions containing as an active ingredient N-(Z-acetylamino-3,5-dibromo-benzyl) N-ethyl-B-amino-propionic acid-morpholide or a non-toxic acid addition salt thereof, or a compound of the formula 3,769,408 Patented Oct. 30, 1973 wherein Hal is chlorine or bromine,

R is hydrogen, chlorine or bromine,

R is alkyl of 1 to 4 carbon atoms, phenyl or benzyl, and

R is hydrogen, alkanoyl of 2 to 4 carbon atoms, benzoyl,

chlorobenzoyl, methoxybenzoyl, nicotinoyl or isonicotinoyl,

or a non-toxic, pharmacologically acceptable acid addition salt thereof.

The active ingredients may be prepared by a number of different methods involving well known chemical reaction principles, among which the following has proved to be most convenient and efiicient:

By reacting a halo-substituted 2-diacylaminobenzyl halide of the formula Hz-Hal N-Ae Hal Ac wherein R and [Hal have the same meanings as in Formula I and Ac is acyl, with a morpholide of the formula R2 HN/ o i)n b wherein R has the same meanings as in Formula I and n is 1 or 2.

The reaction is carried out in the presence of an agent capable of tying up or neutralizing the hydrohalic acid released by the reaction, such as an inorganic or tertiary organic base or also a stoichiometric excess of the aminocarboxylic acid reagent III. The reaction is preferably performed in the presence of an inert organic solvent, such as carbontetrachloride, chloroform, ethanol, acetone, benzene or toluene, and it proceeds particularly rapidly at elevated temperatures, preferably at the boiling point of the particular solvent which is employed. If an excess of the aminocarboxylic acid III or a tertiary organic base is used as the hydrohalic acid-binding agent, these may simultaneously serve as the solvent medium.

The active ingredients can also be prepared by reaction of a correspondingly substituted benzylamino carboxylic acid with a correspondingly substituted amine via the mixed anhydride with ethyl chloroformate.

In those instances where the above method yields N-(Z- diacetylamino 3,5 dibromo-benzyl)-N-ethyl-B-arninopropionic acid-morpholide or a compound of the Formula I wherein the amino group attached to the benzene nucleus is diacylated, one of these acyl groups may, if desired, be split ofi according to conventional methods. On the other hand, if R in Formula I is hydrogen, this hydrogen atom may, if desired, be replaced by an acyl group by customary methods.

The starting materials, that is, compounds of the Formulas II and III, are described in the prior art or may readily be prepared by processes described in the prior art.

For instance, a halo-substituted 2-diacylaminobenzyl halide of the Formula 11 may be prepared by reacting a corresponding halo-substituted 2 diacylamino-toluene with N-bromo-succinimide or with a halogen under ultraviolet irradiation. with a halogen under ultraviolet irradiation.

N (2 acetylamino 3,S-dibromo-benzyl)-N-ethyl-fiamino-propionic acid-morpholide and the compounds of the Formula I above form addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid, 8-chloro-theophylline or the like.

The following example illustrate the preparation of various active ingredients for the compositions according to the present invention.

EXAMPLE 1 N-(2-b enzoylamino-6-chloro-benzyl)-N-methyl-glycinemorpholide (a) A mixture consisting of 9.75 gm. of 6-chloro-2-dibenzoylamino-benzyl bromide, 2.34 gm. of sarcosine methyl ester, 3.18 ml. of triethylamine and 250 ml. of chloroform was refluxed for five hours. Thereafter, an additional 0.5 gm. of sarcosine methyl ester was added, and the mixture was again refluxed for five hours. Subsequently, the chloroform was evaporated in vacuo, the residue was taken up in ethylacetate, the insoluble matter was separated by filtration, and the filtrate was again evaporated in vacuo. The residual oil was dissolved in methanol, the solution was admixed with 25 ml. of 2 N sodium hydroxide, and the mixture was allowed to stand overnight at about 20 C. Thereafter, the methanol was evaporated in vacuo, and the residual aqueous solution was adjusted to pH 2 with 2 N hydrochloric acid, then extracted with ethyl acetate and then adjusted to pH 6 with 2 N sodium hydroxide. The crystalline product precipitated thereby was collected by vacuum filtration and recrystallized from water, yielding N-(2-benzoylamino-6- chloro-benzyl)-N-methyl-glycine, M.P. 150--152 C.

(b) 80.7 gm. of N-(2-benzoylamino-6-chlorobenzyl)- N-methyl-glycine and 38 ml. of triethylamine were dissolved in 1 liter of dry chloroform. While stirring the resulting solution at to 5 C., 23.4 ml. of ethyl chloroformate were rapidly added dropwise, and the mixture was stirred for 40 minutes more at -l5 to 5 C. Thereafter, 50 ml. of morpholine were added all at once, and the mixture was allowed to stand at C. for 20 hours. Subsequently, the chloroformic reaction solution was washed three times with brine, dried over mangesium sulfate and evaporated in vacuo, and the oily residue was taken up in ether, whereupon it crystallized. The crystalline product was recrystallized from methanol, yielding N (2 benzoylarnino-6-chlorobenzyl)-N-methyl-glycinemorpholide, M.P. 1225-123 C., of the formula The product was dissolved in isopropanol, and the solution was acidified with anhydrous hydrochloric acid, yielding the hydrochloride, M.P. 206208 C. (decomp.).

EXAMPLE 2 was prepared from N (2-acetylamino-3,S-dibromo-benzyl)-N-methyl-glycine and morpholine.

EXAMPLE 3 Using a procedure analogous to that described in Example 1, N (2 acetylamino-4-bromo-benzyl)-N-methylglycine-morpholide, M.P. 138140 C., was prepared from N (2-acetylamino-4-bromo-benzyl)-N-methyl-glycine and morpholine.

EXAMPLE 4 Using a procedure analogous to that described in Example 1, N-(2-acetylamino-S-bromo-benzyl)-N-methylglycine-morpholide, M.P. 151l54 C., was prepared from N- (2-acetylamino-S-bromo-benzyl -N-methyl-glycine and morpholine.

' EXAMPLE 5 Using a procedure analogous to that described in Example 1, N-(2-acetylamino-3,S-dibromo-benzyl)-N-ethylglycine-morpholide, M.P. 138 C., was prepared from N- (2-acetylamino-3,S-dibromo-benzyl)-N-ethyl-glycine and morpholine.

EXAMPLE 6 Using a procedure analogous to that described in Example l, N-(2-acetylamino-3,S-dibromo-benzyl)-N-(nbutyl)-glycine-morpholide, M. P. 134 C., was prepared from N-(2-acetylamino-3,5-dibromo-benzyl)-N-(n-butyl)- glycine and morpholine.

EXAMPLE 7 Using a procedure analogous to that described in Example 1, N-(2-acetylarnino-3,S-dibromo-benzyl)-N-benzyl-glycine-morpholide, M.P. 102 C., was prepared from N-(2-acetylamino-3,S-dibromo-benzyl) N-benzyl-glycine and morpholine.

EXAMPLE 8 Using a procedure analogous to that described in Example 1, N-(2-acetylamino-3,5-dibromo-benzyl)-N-ethyl B-amino-propionic acid-morpholide, M.P. C., was prepared from N-(2-acetylamino-3,S-dibromo-benzyl)-N- ethyl-fi-amino-propionic acid and morpholine.

EXAMPLE 9 Using a procedure analogous to that described in Example 1, N-(2-acetylamino-6-chloro-benzyl)-N-methylglycine-morpholide, M.P. 166167 C., was prepared from N (Z-acetylamino-6-chloro-benzyl)-N-methyl-glycine and morpholine.

EXAMPLE 10 Using a procedure analogous to that described in Example 1, N-(2-acetylamino-6-chloro-benzyl)-N-ethyl-glycine-morpholide, M.P. 141 C., was prepared from N- (2-acetylamino-6-chloro-benzyl)-N-ethyl-glycine and morpholine.

EXAMPLE 11 Using a procedure analogous to that described in Example N (2-acetylamino-6-chloro-benzyl)-N-(n-propyl)-glycine-morpholide, M.P. 154-155 C., was prepared from N (2-acetylamino-6-chloro-benzyl)-N-(n-propyl)- glycine and morpholine.

EXAMPLE 12 Using a procedure analogous to that described in Example 1, N-(2-acetylamino-6-chloro-benzyl)-N-isopropylglycine-morpholide, M.P. 170 C., Was prepared from N (2-acetylamino-G-chloro-benzyl)-N-isopropyl-glycine and morpholine.

EXAMPLE 13 Using a procedure analogous to that described in Example 1, N-(2-acetylamino-6-chloro-benzyl)-N-isobutylglycine-morpholide, M.P. -166" C., was prepared from N-(Z-acetylamino-6-chloro-benzyl)-N-isobutyl-glycine and morpholine.

Using a procedure. analogous to .that described. in Ex, ample 1, N-(2-acetylamino-6-chloro-benzyl)-N-benzylglycine-morpholide, M.P. 117-11'8 C., was prepared from N-(Z-acetylamino-6-chloro-benzyl)-N-b enzyl-glycine and morpholine.

EXAMPLE 16 Using a procedure analogous to that described in Example l, N- (2-acetylamino-6-chloro-benzyl)-N-phenylglycine-morpholide, M.P. 166-167 C., was prepared from N-(2-acetylamino-6-chloro-benzyl)-N-pheny1-glycine and morpholine.

EXAMPLE 17 Preparation of N-(2-amino-6-chloro-benzyl)- N-methyl-glycine-morpholide A mixture of 15.0 gm. of N-(2-amino-6-chloro-benzyl)- N-methyl-glycine, 17.5 gm. of 2-hydroxy-1-naphthaldehyde and 1 liter of absolute ethanol was boiled. The water formed thereby was continuously azeotropically distilled OE, and fresh absolute ethanol was continuously added to the reaction mixture at the same rate as the water distilled oflf. After about three hours of boiling the reaction mixture was allowed to cool, the yellow crystalline precipitate formed thereby was separated by vacuum filtration, and the filter cake was washed with ethanol and ether, yielding N-[2-(2-hydroxy-1-naphthal-amino)-6- chloro-benzyl]-N-methyl-glycine, M.P. 185-187 C. (decomp.).

5.9 gm. of this intermediate product were dissolved in 100 cc. of absolute chloroform. The resulting solution was then admixed at C. in an atmosphere of nitrogen and while stirring with 2.2 cc. of triethylamine and 1.5 cc. of ethyl chloroformate. The mixture was allowed to stand for twenty minutes at -10 C., 2.7 cc. of morpholine were added, and the reaction was allowed to proceed for one hour at C. in an atmosphere of nitrogen. Thereafter, the reaction mixture was freed from solvent in vacuo and, to remove the amino-protective group, it was stirred for one and a half hours with 70 cc. of 0.5 N hydrochloric acid. The regenerated hydroxynaphthaldehyde was extracted with chloroform. The aqueous phase was neutralized with 35 cc. of 1 N sodium hydroxide, whereby a precipitate formed which was separated by vacuum filtration, washed with water and recrystallized from a mixture of methanol and water. The product was identified to be N-(2-amino-6-ch1oro-benzyl)-N- methyl-glycine-morpholide, M.P. 116-118 C.

EXAMPLE 18 Using a procedure analogous to that described in Exam ple 1, N- (2-benzoy1amino-6-chloro-benzyl)-N-methylglycine-morpholide, M.P. 122.5-123 C., was prepared from N-(Z-benzoylamino-'6-chloro-benzyl)-N-methyl-glycine and morpholine.

EXAMPLE 19 Preparation of N-(2-propionylamino-6-chloro-benzyl)-N- methyl-glycine morpholide A mixture of 2.0 gm. of N-(2-arnino-6-chloro-benzyl)- N-methyl-glycine-morpholide, 50 cc. of chloroform and 1 cc. of propionic acid anhydride was refluxed for one hour. Thereafter, the reaction solution was cooled, the excess unreacted anhydride was destroyed by adding methanol, the solution was evaporated in vacuo, the residue was taken up in chloroform, and the solution was washed with 1 N sodium hydroxide and water. The red solution thus obtained was decolorized by stirring with silicagel, filtered, the filtrate was evaporated, and the residue was recrystallized from a mixture of isopropanol and water. The product had a melting point of 86-8'8 C. and was identified to be N-(2-propionylamino-6-chloro-benzyl)-N-methylglycine-morpholide.

6 EXAMPLE 2o 1 Preparation of N-(2-butyrylamino-6-chloro-benzyl)-N- methyl-glycine-morpholide To a mixture of 2.0 gm. of N-(2-amino-6-chlorobenzyl)-Nmethyl-glycine-morpholide and 1.2 cc. of triethylamine in 50 cc. of chloroform at -10 C. there were added 0.85 cc. of freshly distilled butyryl chloride. After two hours at room temperature the solution was washed with 1 N sodium hydroxide and water, dried, and evaporated in vacuo. The residue was dissolved in as little methanol as possible and water was added carefully thereto until the solution turned turbid. The precipitate formed was separated by vacuum filtration, washed with water and recrystallized from a mixture of isopropanol and water. It had a melting point of 67-68" C. and was found to be N-(2-butyrylamino-6-chloro-benzyl)-N-methyl-glycine-morpholide of the formula CI CH3 crn-N 0 CH -i P-N b 'EXLAM-PLE 21 EX AMPLE 22 Preparation of N-(2-benzoylamino-6-chloro-benzyl)-N- methyl-glycine-morpholide A mixture of 17.4 gm. of Z-dibenzoylamino-fi-chlorobenzyl bromide, 14.4 gm. of sarcosine-morpholide, 6.4 cc. of triethylamine and 500 cc. of carbon tetrachloride was refluxed for seven hours. Thereafter, the triethyl-ammonium bromide which had precipitated out was separated by vacuum filtration, and the filtrate was evaporated to dryness. The residue was recrystallized first from isopropanol and then from methanol, whereby the side product, N-benzoyl-sarcosine-morpholide, remained in solution. The recrystallized product had a melting point of 122.5-123 C. and was found to be identical with the product obtained in Examples 1 and 21.

The product was dissolved in isopropanol and the solution was acidified with anhydrous hydrochloric acid, yielding the hydrochloride of N-(2-benzoylamino-6-chlorobenzyl)-N-methyl-glycine-morpholide, M.P. 206-208 C. (decomp.).

EXAMPLE 23 Using a procedure analogous to that described in Example 20, N-[2-(p-chloro-benzoyl-amino)-6-chloro-benzyl]- N-methyl-glycine-morpholide, M.P. 126-128 C., of the formula CHr-N CHaC ON 2) 7 methyl glycine morpholide and p methoxy benzoyl chloride.

EXAMPLE .25

Preparation of N-(2-nicotinoylamino-fi-chlorobenzyl)-N-methyl-glycine-morpholide 5.53 gm. of nicotinic acid and 6.3 cc. of triethylamine were dissolved in 150 cc. of chloroform, the solution was cooled to -10 C. and, while stirring, 4.36 cc. of ethyl chloroformate were added thereto. The mixture was maintained for 20 minutes at -l to C., and then a solution of 13.0 gm. of N-(2-amino-6-chloro-benzyl)-N- methyl-glycine-morpholide in 50 cc. of chloroform was added. The reaction mixture was allowed to stand at room temperature overnight, insoluble matter was filtered oif, and the filtrate was washed with an aqueous potassium bicarbonate solution. The chloroform phase was dried over magnesium sulfate, evaporated to dryness in vacuo, and the residue was recrystallized first from ether and then from isopropanol. The purified product had a melting point of 122 C. and was identified to be N-(Z-nicotinoyl-amino-fi-chloro-benzyl) N methyl-glycine-morpholide of the formula CI-h-N CHa-C ON EXAMPLE 26 Using a procedure analogous to that described in Example 25, N-(2-isonicotinoylamino-6-chloro-benzyl)-N- methyl-glycine-morpholide, M.P. 136 C., was prepared from N-(2-amino-6-chloro-benzyl) N methyl-glycinemorpholide and isonicotinic acid.

EXAMPLE 27 Using a procedure analogous to that described in Example 22, N-(2-benzoylamino6-chloro-benzyl)-N-ethylglycine-morpholide, M.P. 109-111" C., was prepared from 2-dibenzoylamino-6-chloro-benzyl bromide and N-ethylglycine-morpholide.

EXAMPLE 28 Using a procedure analogous to that described in Example 22, N-(2-benzoylamino-6-chloro-benzyl)-N-isopropyl-glycine-morpholide, M.P. 125-127 C., was prepared from Z-dibenzoylamino-6-chloro-benzyl bromide and N- isopropyl-glycine-morpholide.

EXAMPLE 29 Using a procedure analogous to that described in Example 22, N-(2-benzoylamino-fi-chloro-benzyl)-N-phenyl-glycine-morpholide, M.P. 183l85 C., was prepared from 21-dibenzoylamino-6-chloro-benzyl-bromide and N- phenyl-glycine-morpholide.

EXAMPLE 30 Using a procedure analogous to that described in Example 1, N-(2-benzoylamino-S-chloro-benzyl)-N-methylglycine morpholide, was prepared from N-(Z-benzoylamino-S-chloro benZyD-N-methyI-glycine and morpholine. Its hydrochloride had a melting point of 215 C. (decomp.). EXAMPLE 31 braced by Formula Iabove, and their non-toxic, pharmacologically acceptable acid addition salts have useful pharmacodynamic properties. More particularly, they exhibit antitussive and respiration-stimulating activities in warm-blooded animals, such as rats resp. cats. In addition, they are useful as intermediates in the preparation of pharmacologically useful benzodiazepines and benzodiazocines.

For pharmaceutical purposes, the compounds are administered to warm-blooded animals perorally, parenterally or rectally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one dosage unit of the active ingredient, such as tablets, coated pills, solutions, syrups, suspensions, capsules, wafers, suppositories and the like. One dosage unit of an active ingredient according to the intant invention is from 0.166 to 5.0 mgm./kg, preferably 0.33 to 1.67 mgm./kg. body weight.

The following examples illustrate a few dosage unit compositions according to the present invention. The parts are parts by weight, unless otherwise specified.

EXAMPLE 32 Syrup The syrup was compounded from the following ingredients:

Distilled water, q.s. ad 100.0 parts by vol.

Compounding procedure. The distilled water was heated to C., and then the benzoic acid, the tartaric acid, the ammonium chloride, the glycine compound, the food colors and the sugar were successively dissolved therein. The resulting syrup was cooled to room temperature, the sodium pyrosulfite was dissolved therein, and then a mixture of the flavoring and the ethanol was stirred in. The finished syrup was filtered through a suitable filter. 5 cc. of the finished syrup contained 25 mgm. of the active ingredient, and when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good antitussive and respiration-stimulating effects.

EXAMPLE 33 Drop solution The solution was compounded from the following ingredients:

Parts N (2 acetylamino 6 chlorobenzyl) N (nbutyl)-glycine morpholide 5.0 p-Hydroxybenzoic acid methyl ester 0.07 p-Hydroxybenzoic acid propyl ester 0.03 Polyvinylpyrrolidone 5.00

Distilled water, q.s. ad 100.00 parts by vol.

Compounding procedure-The p-hydroxybenzoic acid esters, the polyvinylpyrrolidone and the glycine compound were successively dissolved in a sufiicient amount of distilled water at 80 C. The resulting solution was cooled to room temperature, diluted with additional distilled water to the desired volume, and the soltuion was filtered until free from suspended particles. 1 cc. of solution contained 50 mgm. of the active ingredient and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good antitussive and respiration-stimulating effects.

EXAMPLE 34 Coated pills The pill cores were compounded from the following ingredients:

Compounding procedure. The glycine-morpholide compound, the lactose and the potato starch were intimately admixed with each other, the mixture was moistened with an aqueous 12.5% solution of the polyvinylpyrrolidone, and the moist mass was forced through a 1.5 mm-mesh screen. The resulting granulate was dried at 45 C. and again passed through a 1.0 mm.-mesh screen. The dry granulate was then thoroughly admixed with the magnesium stearate, and the mixture was compressed into 220 mgm.-pill cores, which were subsequently coated with a thin shell consisting essentially of talcum and sugar. The coated pills were finally polished with beeswax. Each pill contained 25 mgm. of the active ingredient and, when administered perorally to a warmblooded animal of about 60 kg. body weight in need of such treatment, produced very good antitussive and respiration-stimulating effects.

EXAMPIJE 35 Tablets The tablet composition was compoundsd from the following ingredients:

compound, the lactose and the potato starch were intimately admixed with each other, and the mixture was moistened withan aqueous solution of the gelatin. The most mass was forced through a 1.5 mm.-mesh screen, and the resulting granulate was dried at 45 C. and again passed through the screen. The dry granulate was thoroughly admixed with the silicic acid and with the magnesium stearate, and the mixture was compressed into 400 mgm.-tablets. Each tablet contained 50 mgm. of the active ingredient and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good antitussive and respiration-stimulating effects.

Total 1700.0

Compounding procedure.The finely powdered glycine-morpholide compound was stirred in the cocoa butter, which had previously been melted and cooled to 40 C., and the mixture was homogenized. The composition was then poured at about 37 C. into cooled suppository molds, each holding 1700 mgm. of the mixture. Each suppository contained 25 mgm. of the active ingredient and, when administered by the rectal route to a warmblooded animal of about 60 kg. body weight in need of such treatment, produced very good antitussive and respiration-stimulating effects.

EXAMPLE 37 Hypodermic solution The solution was compounded from the following ingredients:

Parts N (2-acetylamino-6-chlorobenzyl)-N-(n-butyl)- glycinemorpholide Tartaric acid 2.0 Sorbitol 50.0

Distilled water, q.s. ad 1000.0 parts by vol.

Compounding procedure.The tartaric acid, the glycine-morpholide compound and the sorbitol were successively dissolved in a sufiicient amount of warm distilled water. The solution was cooled to room temperature, diluted with distilled water to the desired volume, and filtered until free from suspended matter. The solution was then filled into white 1 cc.-ampules, which were then sealed and sterilized for 20 minutes at C. Each ampule contained 20 mgm. of the active ingredient, and when the contents thereof were administered parenterally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, very good antitussive and respiration-stimulating effects were obtained.

Analogous results were obtained when N-(Z-acetylamino-3,5-dibromo-benzyl)-N-ethyl p aminopropionic acid-morpholide, or any one of the other compounds embraced by Formula I above, or a non-toxic acid addition salt thereof was substituted for the particular halo-substituted 2-amino-benzylamine morpholide compound in illustrative Examples 32 to 37. Likewise, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. An antitussive and respiration-stimulating pharmaceutical dosage unit composition consisting essentially of an inert pharmaceutical carrier and an eifective antitussive and respiration-stimulating amount of a compound selected from the group consisting of N-(Z-acetylainino- 3,5-dibromo-benzyl) N ethyl-p-amino-propionic acidmorpholide, compounds of the formula Hal NH-R' wherein Hal is chlorine or bromine, R is hydrogen, chlorine or bromine, R is alkyl of 1 to 4 carbon atoms, phenyl or benzyl, and R is hydrogen, alkanoyl of 2 to 4 carbon atoms, benzaccording to claim 1 wherein said compound is N-(Z-benzoylaniino 6 chloro-benzyl)-N- I methylglycine-morpholide or its hydrochloride.

3. The composition according to claim 1, wherein said compound is N- (2-benzoylamino-6-chloro-benzy1)-N-isopropyl-glycine-morpholide.

4. The composition according to claim 1, wherein said compound is N-(Z-benzoylamino 4 chloro-benzyl)-N methyl-glycine-morpholide.

5. The composition according to claim 1, wherein said compound is N (Z-acetylamino-3,5-dibromo-benzyl)-N- methyl-glycine-morpholide.

6. The composition according to claim 1, wherein said compound is N (Z-acetylamino-fi-chloro-benzyl)-N-isopropyl-glycine-morpholide.

7. The method of suppressing the cough reflex and stimulating the respiration in a warm-blooded animal in need thereof, which comprises administering to said animal an effective antitussive and respiration-stimulating amount of a compound selected from the group consisting of N-(Z-acetylamino 3,5 dibromo-benzyl)-N-ethyl-,8- amino-propionic acid-morpholide, compounds of the formula wherein Hal is chlorine or bromine, R is hydrogen, chlorine or bromine,

12 R isg alkylgof 1 to 4 carbon atoms, phenyl or benzyl, '.,;and;"l,v

R is hydrogen, alkanoyl of 2 to 4 carbon atoms, benzoyl, chlorobenzoyl, methoxybenzoyl, nicotinoyl or isonicotinoyl, r v v References Cited UNITED STATES PATENTS 8/1967 Keck et a1 424248 X 3,448,106 6/1969 Nickletal 424-24sx 3,536,712 10/1970 Keck et a1. 424248 X ALBERT T. MEYERS, Primary Examiner N. A. DREZIN, Assistant Examiner US. Cl. X.R. 42435 8 

